The present invention is directed to a method for treating cardiovascular disease by promoting growth of collateral vessels to increase blood flow to target organs and tissues.
The major component of morbidity and mortality attributable to cardiovascular disease occurs as a consequence of the partial or complete blockage of vessels carrying blood in the coronary vascular system and in peripheral vasculature. When such vessels are occluded, various clinical syndromes may result from death of tissue previously nourished by the occluded vessels or inability of the vessels to transport sufficient blood supply to regions requiring high blood consumption and accompanying nutrients. In some individuals, blood vessel occlusion is partially compensated by the natural process of angiogenesis, in which new conduits are formed to replace the function of the impaired vessels. These new conduits, called xe2x80x9ccollateralxe2x80x9d vessels, may facilitate restoration of blood flow to the deprived tissue, thereby constituting xe2x80x9cnatural bypassesxe2x80x9d around the occluded vessels. However, some individuals are unable to generate sufficient collateral vessels to manage the consequences of diminished blood flow from cardiovascular disease.
At present, blood vessel occlusions are usually treated by mechanically enhancing blood flow or by medical reduction of oxygen demands in the involved tissues or organs. Mechanical enhancements are provided most commonly by (1) employing surgical techniques that attach autologous or synthetic vascular conduits proximal and distal to the areas of occlusion, thereby providing bypass grafts, or (2) revascularization by various means to physically enlarge the vascular lumen at the site of occlusion. These procedures involve such devices as balloons, endovascular knives (atherectomy), endovascular drills, and the like. The surgical approach is accompanied by significant morbidity and even mortality, while the angioplasty-type processes are complicated by recurrent stenoses in 25-35% of cases. Successful mechanical revascularization depends, inter alia on accessibility of the occluding stenosis to such procedures. Clearly, there remains a pressing need for means to stimulate angiogenesis to provide collateral blood flow by non-invasive or minimally invasive procedures.
This invention employs electromagnetic fields (EMF) applied by non-invasive or minimally invasive procedures to modulate blood vessel growth in human or animal vasculature. In positive modulation, external application of energy fields stimulates progressive collateralization by artificially inducing or enhancing biochemical and cellular responses in the tissues permeating the target fields. In this manner, blood flow is restored to coronary and other organ systems, peripheral vasculature and muscle vascular beds through an accelerated formation and/or maturation of newly-generated and enlarged vessels that bypass partially or entirely occluded vasculature by induced angiogenesis.
From a clinical perspective, the choice to use such non-invasive revascularization would be particularly appropriate (1) in patients without reasonable options for mechanical revascularization because of inaccessible location of the stenosis, diffuse vascular disease, or poor overall medical condition for surgical or even endovascular intervention; (2) as an adjunct to surgical or endovascular interventions, in which the anatomy of the patient""s blood vessels precluded revascularization of all ischemic regions (i.e., incomplete revascularization using other modalities); (3) as an adjunct to the application of other mechanical stimuli such as laser channel formation (transmyocardial laser revascularization) which have been found to reduce symptoms of ischemia; (4) as an adjunct to the administration or direct application of genetic or growth factor agents also intended to facilitate vascular growth or angiogenesis; and (5) in patients with ischemic disease and attendant symptoms who are not yet appropriate candidates for the above interventions, thereby favoring a non-invasive procedure and making possible earlier therapy attended by virtual absence of morbidity.
Potential forms of energy fields include electromagnetic fields that are pulsed over a wide range of frequencies, intensities and pulsed waveform shapes (PEMF). Electromagnetic fields may also be generated in a continuously oscillating, non-pulsed manner, thus providing a sinusoidal waveform. Specific combinations of these variables deliver a range of biological effects that can be tailored to desired results. Other energy forms, including pulsed or continuously-generated microwave-radiated energy and ultrasonic energy, may be applied. In the case of PEMF, application involves placement of coils around the regions of tissues in which collateralization is desired. One approach is to embed the coils in a cloth wrap, which may be worn as a garment surrounding the body area of interest. For cardiac applications, a vest-type garment may be fabricated. For peripheral applications a wrap, i.e., either around the leg or arm, can be designed to deliver the desired field to the affected organ or tissue.
The structure of coils contained within such garments or wraps can provide for simple homogeneous, xe2x80x9cflatxe2x80x9d field distributions in three-dimensional space, or may be configured to focus on fields with greater intensity localized near the target area.
The number of wire loops comprising a single coil, or each of several coils, and the electric power used to power these wire loops, should be such that the peak intensity of the field within the region of interest is on the order of 10xe2x88x924-10 T.
These applications of energy fields may be utilized not only as primary therapy but in conjunction with mechanical approaches to revascularization or following standard surgical/endovascular or angioplasty approaches. For example, where such revascularization is partially but inadequately achieved by standard techniques, externally-based fields provide an opportunity for complementary revascularization of target areas.
Apparatus for delivering the desired electromagnetic stimulation to target areas taught herein are readily adapted from well-reported (EMF) technology relating to the skeletal system. Principles of design are to be found, for example, in U.S. Pat. Nos. 4,266,532, 3,890,953 and 3,915,151. This applies not only to the basic structure employed in the delivery system but also for the ranges of parameters, as discussed herein. Of particular interest for its comprehensive coverage of electromagnetic therapy is Bassett, xe2x80x9cFundamental and Practical Aspects of Therapeutic Uses of Pulsed Electromagnetic Fields (PEMFs),xe2x80x9d Critical Reviews in Biomedical Engineering, 17:451, Issue 5 (1989). Also of interest in refining parameters based on target location and environment, are the following: Norton, xe2x80x9cPulsed Electromagnetic Field Effects on Chondroblast Culture,xe2x80x9d Reconstr. Surg. Tramaut., 19:70 (1985); Detlavs et al., xe2x80x9cExperimental Study of the Effects of Radiofrequency Electromagnetic Fields on Animals With Soft Tissue Wounds,xe2x80x9d Sci. of Total Environ., 180:35 (1996); Lin et al., xe2x80x9cEffects of Pulsing Electromagnetic Fields on the Ligament Healing in Rabbits,xe2x80x9d J. Vet. Med. Sci. 54(5):1017 (1992); Goats, xe2x80x9cPulsed Electromagnetic-(short-wave) Energy Therapy,xe2x80x9d Br. J. Sp. Med. 23:213; Glassman et al., xe2x80x9cEffect of External Pulsing Electromagnetic Fields on the Healing of Soft Tissue,xe2x80x9d Annals of Plast. Surg. 16(4):287 (April 1986); Watkins et al., xe2x80x9cHealing of Surgically Created Defects in the Equine Superficial Digital Flexor Tendon: Effects of Pulsing Electromagnetic Field Therapy on Collagen-type Transformation and Tissue Morphologic Reorganization,xe2x80x9d Am. J. Vet. Res. 46(10):2097 (1985), and Zoltan, xe2x80x9cElectrical Stimulation of Bone: An Overview,xe2x80x9d Seminars in Orthopaedics 1(4):242 (1986).
The use of PEMF and local application of ultrasonic energy have been described as providing enhancement of fusion rates of bony fractures, as well as accelerating rates of wound healing. U.S. Pat. No. 5,524,624. Such procedures have shown significant promise in diabetes, tobacco use, or other conditions which appear to deter natural bone healing or wound healing responses. They have, however, suggested no extension of the electromagnetic phenomenon in circumstances where positive or negative modulation of angiogenesis can provide dramatic opportunities for addressing problems of (1) occlusions in the coronary and other organ systems and peripheral vasculature, and (2) blood-dependent tumorous tissues.